Project Summary Even with effective, safe, and simple antiretroviral therapy (ART) regimens and effective pre-exposure prophylaxis (PrEP) for HIV treatment and prevention, the US continues to have around 40,000 new HIV diagnoses each year. Among people with HIV, many experience barriers to accessing needed services and experience poor clinical outcomes, often exacerbated by geographic, racial, and economic disparities. Along with the high costs of care, these disparities contribute to ongoing incidence and low rates of diagnosis, engagement in HIV care, and virologic suppression. Earlier this year, DHHS announced a new plan to End the HIV Epidemic (EHE) in the US, with a target to decrease new infections by 90% within ten years, prompting new efforts around how to best mobilize and utilize resources towards this goal. This competing continuation proposes to expand upon the Cost-effectiveness of Preventing AIDS Complications (CEPAC) Model, a computer microsimulation model of HIV disease prevention and treatment, to identify the most effective and cost-effective combination of strategies to end the HIV epidemic in the US. In addition to evaluating emerging biomedical therapies for HIV and interventions along the continuum of HIV care, the research team will work with the public health departments of Los Angeles County, California, and Fulton County, Georgia, to allow for assessment of specific interventions tailored to the epidemic in different jurisdictions. This proposal has two specific aims: Aim 1. To investigate the clinical impact, cost, and cost-effectiveness of interventions throughout the HIV care continuum, including PrEP for prevention, engagement in care, and new treatment regimens. Aim 2. To evaluate the clinical impact, cost, and cost-effectiveness of comprehensive efforts to reach the End the HIV Epidemic targets in the US, and to develop optimization models to assess the most efficient approach to reaching these goals. Aligned with the research priorities of the NIH Office of AIDS Research to reduce the incidence of HIV and evaluate next-generation HIV therapies, the CEPAC team will leverage the strengths of mathematical simulation modeling along with new optimization methods. This effort will highlight the value of new HIV therapies and continuum of care interventions and provide evidence to inform decisionmakers about the most effective strategies to reach the End the HIV Epidemic targets.